tbuckley/cabot-search huggingface dataset:
PATH-01. Infant-Type Hemispheric Glioma: New Molecular Alterations and Precision-Medicine Treatment
Authors: Wanming Hu, Li Yuan, Jing Zeng
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Infant-type hemispheric glioma, harboring alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET, is a new subtype of Pediatric-type diffuse high-grade gliomas in the 2021 WHO classification of CNS tumors. It has important clinical therapeutic value with specialized therapeutic drugs. Here, we presented 3 cases of infant-type hemispheric glioma. Patient1 with EML4-ALK fusion which often appeared in lung cancer, the other 2 patients have new molecular alterations which has not been reported before (Patient2 has both NTRK1-TP53/TP53-NTRK1 fusions and p53 protein showed characteristic cytoplasm positive; Patient3 presented a brand-new ALK-QKI fusion combined with ALK mutation and focal SMARCB1 deletion. All these 3 cases received corresponding targeted therapy and have a good recovery and normal neurologic function till now. METHOD: Immunohistochemistry, fluorescent in situ hybridization and whole-transcriptome sequencing. RESULTS: Case 18 months, male, right semiovale center occupation. Histopathology: High-grade neuroepithelial neoplasm. IHC: GFAP(only few cells+), Olig2(-), S100(+), CD56(+), Syn(-), NSE(focal+), NeuN(-), CD34(-), INI-1(+), Ki67(10%+). Characteristic Molecular Information: EML4-ALK fusion. Follow-up: 15 months, alive. Case 2: 3 years, female, insular lobe occupation.Histopathology: Gliosarcoma. IHC: GFAP(partly+), Olig2(partly+), Vimentin(+), P53(cytoplasm+), pan-TRK(+), Ki67(25%+). Reticular fiber staining showed biphasic tissue pattern with reticulin-rich sarcomatous and reticulin-free gliomatous elements. Characteristic Molecular Information: NTRK1-TP53 and TP53-NRTK1 fusion. Follow-up: 27 months, alive. Case 3: 3 years, male, left parietal occipital lobe occupation. Histopathology: GBM and AT/RT. IHC: GFAP(partly+), Olig2(partly+), INI-1(partly-), BRG1(+), SYN(-), CD34(-), BRAF(-), S100(-), CK(-), H3K27M(-), IDH1(-), P53(40%+), ATRX(+), pan-TRK(-), ALK(+), Ki67(30%+). Characteristic Molecular Information: ALK mutation, ALK-QKI fusion, RAD51C mutation and focal SMARCB1(INI-1) deletion. Follow-up: 14 months, alive. CONCLUSION: Infant-type hemispheric glioma is a special kind of glioma, which is particularly suitable for precision-medicine treatment approaches. Their overall survival is good compared with other three pHGG subtype.
MEDB-36. Clinical and molecular heterogeneity within<i>MYC</i> and<i>MYCN</i> amplified medulloblastoma
Authors: Edward Schwalbe, Janet Lindsey, Rebecca Hill, Stephen Crosier, Sarra Ryan, Daniel Williamson, Marcel Kool, Till Milde, Stefan Pfister, Simon Bailey, Steven Clifford
Journal: Neuro-Oncology (2022)

Abstract MYC and MYCN are the most commonly amplified oncogenes in medulloblastoma. Their overall association with a poor prognosis has supported their adoption as high-risk disease biomarkers in trials. However, emerging evidence suggests that certain patients with MYN/MYCN focally-amplified tumours can achieve long-term survival and therefore may suffer unnecessary late-effects associated with intensified therapies. To investigate this heterogeneity, we characterised the molecular and clinico-pathological features of curated cohorts of MYC (n=64) and MYCN (n=95) amplified tumours, drawn from &amp;gt;1000 diagnostic cases, and assessed their associations with disease outcome. Within the MYCN-amplified cohort, survival was related to molecular group; patients with MYCNGrp3 or MYCNGrp4 tumours with no other clinico-pathological risk factors (subtotal resection (STR), metastatic disease, LCA pathology) were intermediate-risk (n=25;70% 5-year PFS). In contrast, a very-high-risk group was defined by positivity for MYCNSHH, STR and/or LCA (n=64;32% 5-year PFS). 22/35 assessable MYCNSHH harboured TP53 mutations; 9/12 with data were germline. MYCGrp3 represented the majority (46/58; 79%) of molecularly-grouped MYC-amplified tumours. Importantly, while radiotherapy receipt conferred a modest survival advantage, for MYC-amplified tumours with additional clinico-molecular risk factors (LCA, metastasis, STR, Grp3), survival was dismal, irrespective of radiotherapy receipt. A very-high-risk group of MYC-amplified tumours was identified (n=51;10% 5-year PFS), defined by positivity for ≥1 additional risk factors (STR, LCA and/or metastasis). Alternatively, membership of subgroups II/V defined a smaller, very-high-risk patient group (n=28;7% 5-year PFS). Long-term survival was seen in the majority of remaining MYC-amplified tumours negative for these specified features (61% 5-year PFS; high-risk). MYC and MYCN-amplified medulloblastomas are biologically heterogeneous with diverse clinical outcomes. Molecular subgroup assignment and established clinical features are critical for their improved stratification. Patient subgroups identified may be eligible for therapy de-escalation; in contrast, the very-high-risk patient groups are incurable using current therapies and urgently require novel experimental treatment strategies upfront.
Errors in the Introduction and Results
Authors: Shabih Manzar
Journal: JAMA Pediatrics (2022)

To the Editor I read with great interest the article by Kaiser et al 1 describing pediatric hospitalization patterns in different hospital setups.In the data presented from 3768 US hospitals (Figure 1 1 ), an estimate of 34 704 of 1 777 023 nonbirth pediatric hospitalizations (1.95%) occurred because of neonatal hyperbilirubinemia (NHB).The prevalence rankings of NHB differed among hospitals (ranking 5 in urban nonteaching hospitals and rural hospitals, 7 in urban teaching hospitals, and 20 in freestanding children's hospitals).On further analysis, NHB constituted 2.42 admissions (3447/1424) per rural hospital, 6.18 (7148/1156) per urban nonteaching hospital, 16.90 (18 844/1115) per urban teaching hospital, and 72.15 (5267/73) per freestanding children's hospital.It was interesting to note that NHB was ranked 20th in freestanding hospitals but the rate of admissions per hospital was high compared with other hospital types.These findings suggested a potential practice variation among these hospitals with regard to the management of NHB.Although published guidelines are available for the management of NHB, 2,3 high variability has been reported. 4 Zhang et al 4 reviewed 12 clinical practice guidelines for the diagnosis and management of NHB and reported differences in clarity of presentation and rigor of development.A possible solution to decrease variability in admission rates for NHB among hospitals is to follow a centralized clinical practice guideline.Rea et al 5 suggested centralization of clinical practice guideline prioritization and development through a government-driven system.This could eliminate discrepancies between overlapping guidelines and enforce the validity of clinical practice guidelines, potentially resulting in less variation in admission rates for NHB and decreasing the health care cost.
Automated H&amp;E image-based detection and prognostic evaluation of HER2 heterogeneity in ER+ breast cancers.
Authors: Satabhisa Mukhopadhyay, Tathagata Dasgupta, Angelene Berwick, Elizabeth Walsh, Michele Cummings, Nicolas M. Orsi
Journal: Journal of Clinical Oncology (2022)

e12517 Background: HER2 amplification or overexpression is negative prognostic factor that occurs in circa 15% of primary invasive breast cancers, with positive results opening up eligibility for HER2 targeted (e.g. trastuzumab) combination therapy. However, HER2 intratumoral heterogeneity has been proposed as an explanation for the development of resistance to anti-HER2 targeted therapy. The aim of this retrospective study was to test the prognostic value of a HER2 heterogeneity index on ER+ breast cancer H&amp;E whole slide images (WSIs). Methods: ER+ breast cancers slides ( n=60 cases) of known HER2 status (immunohistochemically assessed over the 0 to 3+ range, with HER2 2+ borderline cases validated by fluorescence in situ hybridization) were digitized on an Aperio AT3 scanner. A subset of these patients ( n=29) was accounted for by HER2 amplified/borderline cases. A HER2 heterogeneity index was tested and compared to standard clinical HER2 status in these cases and related to progression free survival (PFS). Survival analyses were performed using Kaplan-Meier (KM; with median cut-off) and Cox Proportional Hazards (as a continuous variable) models. Results: The HER2 heterogeneity index performed better in terms of prognostication than clinical HER2 status alone in relation to PFS (KM P=0.019; HR 8.06, P=0.01 vs. KM P=0.02; HR 6.75, P=0.048). These differences were more pronounced in the HER2 amplified/borderline tumor subset, where the HER2 heterogeneity index outperformed clinical HER2 status (KM P=0.04; HR 6.38, P=0.001 vs. KM P=0.10; HR 0.64, P=0.20). Conclusions: These findings highlight the merit of identifying HER2 heterogeneity from H&amp;E slides alone and establish this index as a robust prognostic factor in determining PFS in ER+ breast tumors. Future work will extend this investigation into ER- tumors and evaluate patient-specific tumor responses to anti-HER2 targeted therapy.
Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021)
Authors: Neeraj Agarwal, Bradley McGregor, Benjamin L Maughan, Tanya B Dorff, William Kelly, Bruno Fang, Rana R McKay, Parminder Singh, Lance Pagliaro, Robert Dreicer, Sandy Srinivas, Yohann Loriot, Ulka Vaishampayan, Sanjay Goel, Dominic Curran, Ashok Panneerselvam, Martin Schwickart, Toni K Choueiri, Sumanta Pal
Journal: The Lancet Oncology (2022)
DREAM3R: Durvalumab with chemotherapy as first-line treatment in advanced pleural mesothelioma—A phase 3 randomized trial.
Authors: Patrick M. Forde, Anna K. Nowak, Peey-Sei Kok, Chris Brown, Zhuoxin Sun, Valsamo Anagnostou, Kenneth John O'Byrne, Sonia Yip, Alistair Cook, Willem Joost Lesterhuis, Brett Gordon Maxwell Hughes, Nick Pavlakis, Julie R. Brahmer, Hedy L. Kindler, Anne S. Tsao, Marjorie Glass Zauderer, Suresh S. Ramalingam, Martin R. Stockler
Journal: Journal of Clinical Oncology (2022)

TPS8599 Background: Combination PD1/CTLA4 immune checkpoint blockade and platinum-pemetrexed (CP) chemotherapy are standard first-line options for the treatment of unresectable malignant pleural mesothelioma (MPM). Two recent, single-arm, phase 2 trials (DREAM and PrE0505) combining the PD-L1 inhibitor durvalumab and standard first line CP both exceeded pre-specified efficacy criteria. The Phase 3 DREAM3R trial aims to determine the effectiveness of including durvalumab with first line CP chemotherapy in advanced MPM. Methods: Treatment-naïve patients with advanced MPM will be randomized (2:1) to either durvalumab 1500 mg every 3 weeks plus chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 5 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles (Arm A), followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, versus doublet chemotherapy alone for 4-6 cycles with all patients monitored for progression. The target sample size is 480 patients recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival (OS) is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Key eligibility criteria include: MPM of any histological subtype; measurable disease per RECIST 1.1 modified for mesothelioma (mRECIST 1.1); ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for MPM, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Patients will be further stratified at randomization by: Age (18-70 years vs. &gt; 70), sex, histology (epithelioid vs. non-epithelioid), planned platinum (cisplatin vs. carboplatin) and geographic region (USA vs. ANZ). The primary endpoint is OS. Secondary endpoints include progression-free survival; objective tumor response; adverse events; health-related quality of life; and healthcare resource use in ANZ. Tertiary correlative objectives aim to further explore and validate potential prognostic and/or predictive biomarkers (including those identified in the DREAM and PrE0505 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes) via tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The study is active and enrolling in both ANZ and in the US. Clinical trial information: NCT04334759 and ACTRN 12620001199909.
MODL-02. A novel<i>Cre</i>-conditional<i>cMYC</i>-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination.
Authors: Alaide Morcavallo, Karen Barker, Colin Kwok, Jessica K R Boult, Patricia Benites Goncalves da Silva, Konstantin Okonechnikov, Marc Zuckermann, Chiara Gorrini, Thomas S Jacques, Simon P Robinson, Steven C Clifford, William A Weiss, Stefan M Pfister, Daisuke Kawauchi, Louis Chesler
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB), the most common embryonal tumour of the Central Nervous System, occurs in the cerebellum. Treatment regimens involve surgery, craniospinal radiotherapy, and chemotherapy. The greatest mortality is associated with disseminated disease, almost exclusively found in the leptomeningeal space. Unfortunately, knowledge about the aetiology of MB spread is limited and the need for kinder and efficacious therapy remains an unmet goal. Of the four molecular classified MB groups, Group3 (Gr3) MB presents with a high frequency of metastasis at diagnosis, with the worst overall survival. Gr3 MB tumours are dominated by primitive progenitor-like cells and cMYC deregulation; often, p53 deficiency is observed at relapse. To dissect the biology of primary and metastatic Gr3 MB, we have developed a new germline genetically engineered mouse model (GEMM), harbouring cMYC amplification in a Tamoxifen-inducible p53 functional background (Trp53ERTAM strain). A novel LSL-cMYC-CopGFP-Luciferase transgene was integrated into the Rosa-26 locus of the mouse genome. Transgenic mice were crossed with a strain expressing Cre recombinase under the Blbp promoter targeting embryonic neural progenitors, and subsequently bred to Trp53ERTAM mice. As result, the cMYC overexpression was sufficient to generate tumours. Tumour penetrance was observed in all the expected tumour bearing genotypes, with increased aggressiveness in a non-functional p53 background. Bioluminescence imaging demonstrated tumour onset in the brain and dissemination along the spinal cord. CopGFP positive tumour cells were isolated from primary and metastatic tumours. Pathological interrogation confirmed that tumours present large cell/anaplastic (LCA) histology. Analysis of preliminary transcriptional profiling data proved that tumours cluster with human Gr3 MB. Ongoing methylation profiling and multi-omics approaches will inform on the tumour cells of origin and clonal divergence of primary tumour versus metastasis. In conclusion, we have successfully developed a novel immunocompetent mouse model of metastatic Gr3 MB with which we can investigate therapeutic vulnerabilities of MB.
Comparative characterization of single cells and engineered heart tissues from hiPSC-derived cardiomyocyte subtypes
Authors: J Li, A Wiesinger, L Fokkert, B Boukens, A Verkerk, V Christoffels, G Boink, H Devalla
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research council starting grant 714866 and associated proof-of-concept grant 899422 ZonMW and the Dutch Heart foundation MKMD grant 114021512 and Dutch Heart Foundation Dekker fellowship 2020T023 Rationale: Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes represent an excellent in vitro platform to study cardiac development and model patient-specific diseases. However, their widespread application in drug discovery and regenerative approaches has not yet been realized at least in part due to limited comparative characterization of the available cardiomyocyte subtypes and lack of multicellular models that allow assessment of physiologically relevant parameters. Objective Perform comprehensive characterization of hiPSC-derived sinoatrial nodal cardiomyocytes (SANCM), atrial cardiomyocytes (ACM) and ventricular cardiomyocytes (VCM) from 2D and 3D cultures. Methods SANCM, ACM and VCM were generated using directed differentiation protocols. Electrophysiological analysis was performed by single cell patch-clamp. Subtype-specific differences were further characterized by response to neurohumoral agents noradrenaline, and carbachol and If blocker ivabradine. Next, we generated EHTs to evaluate the effect of 3D culturing on cardiomyocyte subtypes and performed optical mapping. To establish a model to study impulse initiation and propagation in vitro, we generated binary EHTs (BIN-EHTs) composed of heteropolar ends of SANCM and ACM. Results Gene expression analysis and single cell electrophysiology confirmed identities of respective cardiomyocyte subtypes. While response to noradrenaline and carbachol were as expected, ivabradine testing showed the functional presence of pacemaker current If in ACM, besides SANCM. After three weeks in culture as EHTs, cardiac structural genes were markedly upregulated in all groups. Optical mapping demonstrated a three-fold increase in conduction velocities in ACM and VCM while SANCM EHTs retained slower conduction velocities recapitulating in vivo differences. In BIN-EHTs, SANCM end of the EHT consistently paced the tissues under baseline conditions. Upon treatment with ivabradine, cycle length of BIN-EHTs increased and impulse initiation switched to ACM end in the majority of tissues. Conclusions We performed comprehensive characterization of hiPSC-cardiomyocyte subtypes, which recapitulated salient features of their in vivo counterparts. BIN-EHT constructs composed of SANCM and ACM are a valuable rudimentary model for investigating impulse formation and propagation in vitro.
Comparative analyses of micro-ultrasound versus MRI-targeted biopsy for the diagnosis of clinically significant prostate cancer. Preliminary results from the prospective US-MIRROR Trial
Authors: S.L.A. Scuderi, A. Stabile, G. Sorce, M. De Angelis, F. Pellegrino, F. Barletta, L. Nocera, G.O. Cirulli, V. Cucchiara, R. Leni, D. Cannoletta, E. Mazzone, A. Pellegrino, G. Rosiello, L. Dambrosio, S. Shariat, N. Fossati, A. Salonia, F. Montorsi, A. Briganti
Journal: European Urology (2022)
Treatment of ureteral stone with LithoEvo device and Vapor Tunnel tool
Authors: M. Maltagliati, L. Berti, U. Besana, C. Buizza, D. Perri, S. Micali, B. Rocco, M.C. Sighinolfi, C. Sciorio, A.L. Pastore, D. Pushkar, A. Govorov, J. Romero Otero, G. Bozzini
Journal: European Urology (2022)
Effects of prior local therapy by radical prostatectomy or radiotherapy on the efficacy and safety of darolutamide in patients with nonmetastatic castration-resistant prostate cancer from aramis
Authors: M. Saar, K. Fizazi, N.D. Shore, M.R. Smith, J-E. Damber, A. Semenov, M.J. Ribal Caparrós, A. Birtle, J. Rigaud, J. Ortiz, A. Schmall, S. Srinivasan, F. Verholen
Journal: European Urology (2022)
Evaluation of flibanserin's benefits and tolerability in women with low libido and a history of breast cancer.
Authors: Somi Javaid, Louise Brown
Journal: Journal of Clinical Oncology (2022)

e18761 Background: After cancer treatment, women with sexual problems are more likely to have a poor quality of life and lack self-esteem. The 2018 American Society of Clinical Oncology guidelines on interventions to address sexual problems in people with cancer lists flibanserin as a treatment option for premenopausal women with low libido and a history of cancer. However, flibanserin's clinical trials excluded women with a history of breast cancer; as a result, there is limited information on benefits and tolerability in this subset of women. This retrospective chart review study was conducted to address this knowledge gap. Methods: Structured data (partner and menopausal status, medications, medical history, and weight) were extracted from predefined fields in the clinic's electronic health record (EHR) system using on-demand reports. Free-text encounter notes served as the data source for unstructured data (benefits and tolerability). Patients with low libido (R68.82 or F52.0) plus a history of breast cancer and ≥1 flibanserin prescription submitted through the clinic’s EHR system (“Flibanserin Plus History of Breast Cancer” [FPHBC] patient), seen at the clinic between September 1, 2015, and August 31, 2021, are included in this analysis. Encounter notes were reviewed to ensure patients had a personal history of breast cancer and terms related to their benefits and tolerability coincided with their actual flibanserin usage. Patients were categorized as either FPHBC-User or FPHBC-Non- Users based on verified flibanserin usage. Results: Findings from the 20 FPHBC-Users are presented in the table below. Conclusions: Flibanserin was generally well-tolerated among FPHBC-Users and most women reported benefits in libido. Unexpected benefits included improved orgasm and other non-sexual benefits. The clinic consulted with all patients’ oncologists before initiating flibanserin which likely contributed to its safe use. It is important to acknowledge that flibanserin is just one component of care, and the benefits and tolerability reported here may or may not be related to treatment alone. Our findings may not generalize to all clinical practices, and more extensive studies are needed to verify these findings.[Table: see text]